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BY 4.0 license Open Access Published by De Gruyter Open Access April 18, 2023

A comprehensive review of non-alkaloidal metabolites from the subfamily Amaryllidoideae (Amaryllidaceae)

  • Abobaker S. Ibrakaw , Akeem O. Akinfenwa and Ahmed A. Hussein EMAIL logo
From the journal Open Chemistry

Abstract

Amaryllidoideae is a subfamily belonging to the Amaryllidaceae and is widely distributed in the southern hemisphere. The subfamily is well known for its content of pharmacologically active alkaloids and represents an important epicenter of Amaryllidaceae-alkaloid diversity. Other metabolites from Amaryllidoideae such as phenolics including flavonoids, lignans, chromones, and acetophenones, in addition to terpenoids and ceramides, have been reported and received less attention compared to alkaloids. Currently, 224 non-alkaloidal compounds have been isolated and identified from ∼7% of the subfamily members. Many of the isolated compounds showed interesting biological activities. Isolation of certain compounds such as flavans and phytosterols from Amaryllidoideae has significant taxonomical value among the Amaryllidaceae subfamilies. This article represents an extensive review of the non-alkaloidal chemical constituents of Amaryllidoideae and their biological activities including a brief discussion of their chemotaxonomical importance.

1 Introduction

The Amaryllidaceae is a family of monocotyledonous flowering plants in the order of Asparagales and was established in 1805; according to the current phylogenetic work, Chase et al. [1] developed the broader (sensu lato) concept of the family. According to the plant list website [2], it contains about 2,362 accepted species, divided into about 80 genera, 17 tribes, and 3 subfamilies; the Agapanthoideae (only one genus, Agapanthus), Allioideae (∼20 genera) and Amaryllidoideae (∼59 genera) [3]. The Amaryllidoideae (formerly recognized as a separate family, Amaryllidaceae J.St.-Hil.) is a widely distributed subfamily of about 850 species. It has a center of diversity in the southern hemisphere, especially South Africa, South America, and the Mediterranean [4,5]. Plants of the Amaryllidoideae were recognized by traditional healers in South Africa and were used to treat different diseases such as, inter alia, cancer and mental health issues. The traditional use of the plant family has been related to their unique alkaloidal contents [4,6,7,8,9]. The plant’s extracts and chemical constituents “mainly alkaloids” are reported to have different biological activities such as antiproliferative, antiinflammatory, antihypertensive, neuroprotection, anticancer, and antimicrobial [4,5,7,10,11,12]. On the other hand, only relatively few reports have been published on other chemical constituents such as terpenoids and flavonoids [4,13,14]. In continuation of the previous reviews on the genera Crinum and Zephyranthes, which reflected the presence of non-alkaloidal chemical constituents [15,16], this review was designed to compile chemical and biological information on non-alkaloidal chemical constituents from plants belonging to the Amaryllidoideae subfamily and to discuss the chemotaxonomical importance concerning other subfamilies among the Amaryllidaceae.

2 Chemistry and biological activities of Amaryllidoideae subfamily constituents

2.1 Flavonoids

Flavonoids are an important class of natural products that have a polyphenolic nature and are widely distributed in higher plants. Flavonoids play a variety of biological roles, such as the color and aroma of flowers, protection from different biotic and abiotic stresses and act as unique UV filters, function as signal molecules, allelopathic compounds, phytoalexins, detoxifying agents, and antimicrobial defensive compounds [17,18]. Chemically, phenylpropanoid formation is a key step in the biosynthesis of flavonoids which react further with malonyl-CoA to form the basic carbon skeleton C6–C3–C6. Different sub-classes of these compounds include flavans, flavanols, chalcones, flavanones, flavones, flavonols, and isoflavones.

2.2 Flavans and 3-flavanols

Flavans are the most common type of flavonoid that are distributed among Amaryllidoideae members (Table 1 and Figure 1). The lipophilic character is reflected by the oxidation pattern of the isolated compounds which is limited to positions C7, C3′, and C4′ and occasionally C2′. Only two glucosylated compounds (13 and 14) were identified from Zephyranthes candida [19]. The C2 position is mostly in the S configuration. The rare C8 methylflavanes (1822) were isolated from a host of different species such as Crinum augustum (21), Hippeastrum x hortorum (18), Hymenocallis littoralis (19), Lycoris albiflora (18, 19), Narcissus pseudonarcissus (18), N. tazetta var. chinensis (18, 22), Pancratium littorale (18), and P. maritimum (20) (Table 1).

Table 1

Non-alkaloidal chemical constituents isolated from Amaryllidoideae and their biological activities

S. no. Species Isolated compounds* Parts**/Origin*** Biological activity/Notes Reference
1. Amaryllis belladonna L. Fla [64, 73]/PA [135] L-F/Eg 73: insecticidal activity against the pink bollworm Pectinophora gossypiella. It causes 48% inhibition of pupation [82]
2. Ammocharis coranica (Ker Gawl.) Herb. Ter [164‒167] B/SA No research on biological activity [83]
3. Boophone disticha (L.f.) Herb. AcP [147] B/SA No research on biological activity [65]
Ter [165, 169] B/SA 165, and 169: weak cytotoxicity against SH-SY5Y cell line [73]
4. B. haemanthoides F.M. Leight. PP [105, 116]/Ter [157‒163] B/SA No research on biological activity [72]
5. Brunsvigia natalensis Baker Fla [1]/Ce [199] No research on biological activity [84]
6. Crinum amabile Donn ex Ker Gawl. Ot [204] B/Tha No research on biological activity [80]
7. C. americanum L. Fla [4, 27] B/Eg 4 inactive against Meth-A and Lewis lung carcinoma tumor cell lines [20]
8. C. asiaticum L. Fla [4, 36, 45, 54]; Ter [171, 173, 183] B/Eg No research on biological activity [25]
9. C. asiaticum L. var. japonicum Baker Fla [4] B/Ko No research on biological activity [85]
Ter [163, 168, 169, 173] B/Jp No research on biological activity [86]
10. C. asiaticum L. var. sinicum (Roxb. ex Herb.) Baker Fla [, 7, 25, 37, 50]/PA [125, 126, 137, 139, 140] Ot [199] B/Ch No research on biological activity [52,53]
No research on biological activity
11. C. augustum Rox ex Ker Gawl. Fla [4, 21, 45, 46]/Ter [164, 165, 172 mixture of 171/173, 183]/Ot [220‒224] B/Eg No research on biological activity [87,88,89,23,37,90,91]
12. C. biflorum Rottb Fla [7, 8, 9, 15, 26, 29, 38, 57]/Ter [171, 172, 180, 175] WP/Ca No antibacterial activity was demonstrated against StA, EF, EC, PM, and PA. [92]
13. C. bulbispermum (Burm.f.) Milne-Redh. & Schweick. Ter [173, 170] B/Eg No research on biological activity [93]
Fla [5, 25, 35, 36, 42, 45]/Ot [200] B/Eg No research on biological activity [94]
Fla [4] B/Eg 4: inhibited the incorporation of 3H-thymidine in Molt 4 cells, with an IC50 value of less than 10 μg/mL, and a cytotoxic effect on Molt 4 cells (ED50, 42 μg/mL) [39]
Fla [47, 52]/PP [106, 115] B/Eg No research on biological activity [95]
Fla [58, 61, 68, 72, 75] F/Eg 61, 68, and 72 had moderate inhibition against CA [lZ = 18, 16, 19 mm, respectively] [42]
Fla [62] L/Eg No research on biological activity [96]
Ot [203] No research on biological activity [8]
14. C. buphanoides Welw. ex Baker AcP [143, 147] B/SA No research on biological activity [66]
15. C. distichum Herb. Fla [3, 4, 11] WP/Ca 3 and 11 displayed moderate antibacterial activity against MRSA and MSSA StA (32 > MIC > 16 μg/mL) [43]
16. C. ensifolium Roxb. ex Ker Gawl. Ter [184] B/Ch 184 cytotoxic against some cancer cell lines and inhibit NF-κB activity with the IC50 of 1.82 µM [75]
17. C. graminicola I.Verd. AcP [147] B/SA No research on biological activity [66]
18. C. jagus (J.Thomps.) Dandy Fla [57] L/Ca 57 protected against tonic-clonic seizures induced by pentylenetetrazol [97]
19. C. latifolium L. PA [125, 126, 132‒134]/Ter [171, 172] –/Ch No research on biological activity [98]
Fla [2, 10, 57, 58]/PA [135, 136, 138] L/Vt No research on biological activity [99,100,101]
Fla [2, 6, 44, 55]/CC [104]/Ter [163] L/Vt 55 and 104: moderately inhibited the tube-like formation of HUVECs. [49]
20. C. macowanii Baker AcP [143, 144] B/SA No research on biological activity [102]
21. C. moorei Hook F. Fla [4]/Ter [171]/CC [92, 93, 96] B/Eg No research on biological activity [103]
22. C. purpurascens Herb. Ter [172] L/Ca No research on biological activity [74]
23. Crinum x powelli Fla [4]/Ot [211] B/Sz 4 and 211: inactive against acetylcholinesterase [104]
24. C. yemense Deflers PA [124]/Ot [210, 215] B/Ym 210 inhibited tyrosinase enzyme at 42.2 μM [81]
25. Cyrtanthus breviflorus Harv. Ter [175‒179] B/SA No research on biological activity [105]
26. C. obliquus (L.f.) Aiton Fla [82‒85] B/SA 82 and 84: weak antioxidants (using DPPH assay) [37]
27. Galanthus caucasicus (Baker) Grossh. Fla [56, 70, 73] WP/Uz No research on biological activity [106]
28. G. nivalis L. Fla [65] F/– No research on biological activity [107]
29. G. nivalis subsp. cilicicus (Baker) Gottl.-Tann. Li [86, 87] WP/Tk No research on biological activity [44]
30. Gethyllis ciliaris (Thunb.) Thunb. CC [98, 99] B/SA 98: weak inhibitor of COX-1 enzyme (IC50 = 262 ± 3.8 μM) [108]
31. Habranthus brachyandrus (Baker) Sealy Fla [1, 2, 7, 15 (2 S ), 23‒25, 30, 43]/Li [90]/AcP [145]/Ot [214] B/Jp 1, 7, and 15: moderate cytotoxic against HL-60 cells with IC50 of 27.9, 42.6, and 19.0 μg/mL, respectively. [40]
32. Haemanthus multiflorus Martyn AcP [148‒156]/Ot [209] B/Jp 146: cytotoxic against HL-60 cell line (IC50 = 20.1 μM) [109]
33. Hippeastrum ananuca Phil. Fla [26, 28] B/Chl No research on biological activity [110]
34. Hippeastrum cultivars Fla [80, 81] F/Ug No research on biological activity [30]
35. H. vittatum (L’Hér.) Herb. PA [131, 137] F/Eg 131: cytotoxic against Hela cells (IC50 = 0.45 μg/mL) [111]
Ce [191‒197] WP/Ch No research on biological activity [76,77]
36. Hippeastrum x hortorum Fla [7, 15, 18, 48] B/Gr Bulbs produce the isolates upon wounding [112]
37. Hymenocallis littoralis (Jacq.) Salisb. Fla [2, 7, 19, 38]/CC [93, 95‒97] WP/Vt No research on biological activity [113]
Fla [69, 73] B/Eg No research on biological activity [27]
38. Leucojum vernum L. Fla [65‒67] F/– No research on biological activity [114]
39. Lycoris albiflora Koidz. Fla [18, 19]/Li [89, 90, 91]/AcP [145, 146] B/Jp 19 and 90: moderately cytotoxic against HL-60 cell line (IC50 = 23.3 and 13.8 μM). [40]
40. L. aurea (L’Hér.) Herb. PP [123] B/Ch 123: protected against H2O2/CoCl2-induced neuronal cell death in dopaminergic neuroblastoma SH-SY5Y cells [115]
41. L. radiata (L’Hér.) Herb. PP [122]/Ot [207] B/Ch No research on biological activity [116,117]
Ot [208] B/Ch No research on biological activity [118]
42. Narcissus poeticus L. PA [127] B/– No research on biological activity [54]
Fla [58, 60] B/– No research on biological activity [26]
43. N. pseudonarcissus L. Fla [1, 2, 18] B/– Compounds were isolated from bulb scales inoculated with Botrytis cinerea [119]
Fla [58, 59, 70, 71, 75‒78] B/– No research on biological activity [120]
44. N. tazetta L. Fla [79] B/– No research on biological activity [121]
45. N. tazetta var. chinensis (M. Roem.) Masam. & Yanagih Fla [2, 4, 5, 7, 11, 12, 18, 22, 31‒34, 38‒41]/PE [107]/PP [117] B/Ch 5, 7, 38, 39, and 40: potent antioxidants against H2O2-induced impairment in SH-SY5Ycells. 2, 4, 7, and 12 demonstrated weak cytotoxicity against A549, HCT116, SK-BR-3, and HepG2 cell lines (IC50 = 16.82–38.51 μg/mL) [21,22]
Fla [73, 74, 79],/PE [108‒114]/PP [118‒121]/PA [128, 129]/Ot [205, 206, 216, 217] F/Jp 108, 111, 114, 118, 120, and 206: potent antimelanogenesis in B16 melanoma 4A5 cells (IC50 = 22.0, 82.5, 74.6, 59.0, 88.0, 59.0 μM resp.) [50]
46. Pancratium biflorum Roxb CC [93, 101, 102, 103]/AcP [146, 155, 156] WP, B/In 153 and 154 stimulated growth and enhanced the viability of Ehrlich ascites tumor cells and have no activity on the production of prostaglandin synthetase and 5-lipoxygenase [46,47,68]
47. P. littorale Jacq. Fla [18] S/Pa 18: free radical scavenger in DPPH assay [122]
48. P. maritimum L. Fla [36, 38, 45, 51] CC [94]/PA [130]/AcP [141, 142] B, F/Eg 130: moderately inhibited M. tuberculosis H37Rv at a concentration of 12.5 µg/mL, and potent cytotoxic against HeLa cells with IC50 = 1.0 µg/mL [123,124]
CC [100, 101]/AcP [141]/Ot [202, 218, 219] B/Eg 101 had antiproliferative (at 50 μM) and weak antimigratory activities against PC-3M [125]
Fla [4, 20, 62, 63]/CC [92, 93, 96], L, B/Eg No research on biological activity [96,126]
PA [137] WP/Tu No research on biological activity [61]
49. Scadoxus pseudocaulus (I.Bj¢rnstad & Friis) Friis & Nordal Fla [38, 49, 53]/Li [88]/Ot [201, 212] WP/Ca 38, 53, and 201 inhibited the growth of EC, PA, CA, CN, CP, and SF with (MIC = 2–16; 8–128; 4–64) respectively38, 201, and 212 had free radical scavengers in DPPH assay (IC50 = 58.2, 76.3, 59.5 μM). 212 inhibited BuChE, with IC50 = 23.5 μM [24,45]
50. Stenomesson variegatum (Ruiz & Pav.) J.F.Macbr. Ter [174, 181, 182] B/Pe No research on biological activity [127]
51. Zephyranthes candida (Lindl.) Herb. Fla [64, 73] F/Jp No research on biological activity [128]
52. Fla [7, 13, 14, 26] WP/Ch 13, 14, and 26 significantly inhibited the LPS-induced NO production in RAW264.7 mouse macrophages with IC50 values of 16.14, 21.52, and 17.34 μM, respectively [19]
Fla [15] WP/Ng 15 inhibited-poliovirus (IC50 = 0.2384 μg/mL) [38]
Fla [2(2 S ), 4(2 S ), 7(2 S ), 15, 73]/Ter [171, 172]/Ce [185‒190]/Ot [213] B/Ch 185 and 187 inhibited the growth of the bacteria SA, EC, AN, CA, and TR [78,79]
53. Z. flava (Herb.) G.Nicholson Fla [6, 15, 16, 17] B/In No research on biological activity [129]

*Compounds: Flav: flavonoids; Li: lignans; CC: chromones and coumarins; PP: phenylpropanoinds and phenylethanoids; PA: phenolic acids; AcP: acetophenones; Ter: terpenoids; Ce: ceramides; Ot: others.

**Part extracted: L: leaves; F: flowers; B: bulbs; S: stem; WP: whole plant.

***Origin (country): Ca: Cameroon; Ch: China; Chl: Chile; Eg: Egypt; Gr: Germany; In: India; Jp: Japan; Ko: Korea; Ng: Nigeria; Pa: Panama; Pe: Peru; SA: South Africa; Sz: Switzerland; Tha: Thailand; Tk: Turkey; Tu: Tunisia; Ug: Uganda; Uz: Uzbekistan; Vt: Vietnam; Ym: Yemen.

Figure 1 
                  Flavans and flavanols.
Figure 1

Flavans and flavanols.

A limited number of 3-flavanols (2330) were isolated from different species, e.g. C. asiaticum L. var. sinicum (25), C. biflorum (26, 29), C. americanum (27), Habranthus brachyandrus (2325, 30), Hippeastrum ananuca (26, 28), and Z. candida (26) (Table 1). The presence of a C3′–C4′ methylenedioxy ring (compounds 2830) increases the lipophilicity of the isolated compounds. It is interesting to note that the rare C3′ methyl flavan-3-ol (27) was isolated once from C. americanum [20].

The structures of 26, 33, and 34 were confirmed by single-crystal X-ray diffraction analysis. Tazettones A‒D (3134), with an unusual rearranged flavan skeleton, were identified in N. tazetta var. chinensis. Biogenetical compounds 3134 have been suggested to be derived from the rearrangement of 8-methylflavan derivatives [21,22].

2.3 Flavanones, dihydroflavonols, chalcones, and flavones

Seven flavanones and one dihydroflavonol have been reported within the period covered in this review (Table 1 contains the references for the compounds listed in Figure 2) and include the C6 and C8 methylated derivatives, farrerol (38) and cyrtomintin (40). The C8 methyl derivatives of naringenin (41) and the C6 derivative of 7-methoxy aromadendrin (49) have also been identified (Table 1).

Figure 2 
                  Flavanones, dihydroflavonols, chalcones, and flavones.
Figure 2

Flavanones, dihydroflavonols, chalcones, and flavones.

Several chalcones and dihydrochalcones have been isolated and it has been suggested that compound 46 (2′,4,4′-trihydroxy-3′-methylchalcone) is the possible precursor to many of the different C8 methylated derivatives 1822 [23]. The C8 (syzalterin, 51) and C8, C6 (sideroxylin/eucalyptin, 53/54) methylated derivatives were isolated from Scadoxus pseudocaulus and C. asiaticum, respectively [24,25].

2.4 Flavonols

The glycosidic forms of kaempferol, quercetin, and isorhamnetin constituted the majority of these isolated compounds in which it was found that the flowers are the main source of flavonols (Table 1 and Figure 3). None of the isolated compounds contain a methyl group at C6 and/or C8, which indicates that the flowers accumulate different types of flavonoids from the bulbs. Rutin (73) was the most common flavonol glycoside isolated. The glycosylation pattern, in general, occurs at C3; however, C7 (60), C3′ (69), and C4′ (63) were isolated as well [26,27].

Figure 3 
                  Flavanols, anthocyanins, and homoisoflavanones.
Figure 3

Flavanols, anthocyanins, and homoisoflavanones.

2.5 Anthocyanins

The color chemistry of Amaryllidoideae flowers has been subjected to some chemical investigation and found that they are linked with certain compounds belonging to the carotenoids, flavones, and/or anthocyanins [28,29]. The colors of different Hippeastrum cultivar flowers have been attributed to the presence of cyanidin 3-O-rutinoside (80) and pelargonidin 3-O-rutinoside (81). According to the CIELab analysis, 80 contributes to the red color while 81 contributes to the orange color [30].

Studies using mainly LC-MS identified different anthocyanins in different Amaryllidoideae flowers. Glycosides of pelargonidin and/or cyanidin have been identified in the genera Lycoris [31,28], Nerine [32], and Hippeastrum [33]. Different color hues such as red, purple, or blue depend not only on the chemical constituents (the pigments) but also on the pH of the media and additionally due to co-pigmentation among others [34,35].

2.6 Homoisoflavanones

The detection of isoflavonoids using LC-MS in different species of Amaryllidoideae showed the presence of daidzein in addition to 14 common isoflavonoids in different parts of the studied plants [36]. The rare homoisoflavanone derivatives (8285) were isolated from Cyrtanthus obliquus bulbs (Table 1 and Figure 3) [37].

Flavonoids are one the most important food constituents. Plants with high flavonoid contents have a great potential for the neutralization of many human pathologies. Flavans 13, 14, and 26 were isolated from Z. candida collected in China and displayed significant inhibitory effects on the LPS-induced NO production in RAW264.7 mouse macrophages with IC50 values of 17.34, 16.14, and 21.52 μM, respectively. The compounds (13, 14, 26) have low cytotoxicity when tested against the same cell line and indicated a high safety margin and the potential as a potent scaffold for the treatment of inflammation [19]. Another flavan derivative (15) was isolated from Z. candida collected in Nigeria and demonstrated antipoliovirus activity with an IC50 of 0.2384 μg/mL and a selectivity index >151 and confirm the potent activity and safety margin of this class of compounds [38].

Compound 4 was isolated from C. bulbispermum and showed a cytotoxic effect on Molt 4 cells (ED50 42 μg/mL) and inhibited the incorporation of 3H-thymidine in Molt 4 cells at IC50 < 10 μg/mL [39].

The low toxicity of closely related flavan derivatives was also confirmed by others [21]. Flavans 2, 4, 5, 7, and 12 were isolated from N. tazetta var. chinensis and demonstrated moderate to weak cytotoxicity. Compound 4 demonstrated weak cytotoxic activity against A549 (IC50 = 36.47 μg/mL), HCT116 (28.48 μg/mL), SK-BR-3 (16.82 μg/mL), and HepG2 (28.71 μg/mL) cell lines, while 7 was active against SK-BR-3 (26.81 μg/mL) and HepG2 (26.50 μg/mL). On the other hand, compounds 2 and 12 showed activity against HCT1 (28.96, 29.18 μg/mL) and HepG2 (34.36, 38.51 μg/mL), respectively [21]. Compound 5, in comparison to 7, 38, 39, and 40, had a more potent antioxidant activity than the positive control, vitamin E and protected SH-SY5Ycells against H2O2-induced impairment [22].

Compounds 19 (from L. albiflora), 1, 7, and 15 (from H. brachyandrus) showed moderate cytotoxic activity against the LH-60 cell line with IC50 values of 6.67, 27.9, 42.6, and 19.0 μg/mL, respectively [40,41].

Compounds 38 and 53 (from Scadoxus pseudocaulus) demonstrated moderate antibacterial and antifungal activities (MIC = 8–128 μg/mL), and 38 showed antioxidant activity using the DPPH assay (IC50 = 58.2 μM) [24].

Compounds 61, 70, and 72 were isolated from C. bulbispermum and showed moderate antibacterial activity against C. albicans [42]. In addition, compounds 3 and 11 (from C. distichum) displayed moderate antibacterial activity [43].

C. obliquus bulbs have been used by South African traditional healers for treatment of different diseases such as pregnancy-related ailments, cystitis, dementia, and leprosy. The antioxidant evaluation of the isolated compounds (8285) was performed using DPPH and FRAP chemical assays and showed strong activity for compounds 82 and 84 [37]. The detection of homoisoflavanones in C. obliquus may need special attention and further investigation for the biological activities associated with this rare skeleton.

2.7 Lignans

The furfuran lignans (+)-epipinoresinol (86) and (+)-pinoresinol (87) were isolated from Galanthus nivalis subsp. cilicicus collected in Turkey [44] (Table 1 and Figure 4). Three neolignans (8991) were identified from L. albiflora [41], while the 4′-glucoside derivative of pinoresinol (88) was from S. pseudocaulus [45]. Compound 90 showed moderate activity against LH-60 with IC50 of 13.8 ± 0.37 μM [41].

Figure 4 
                  Lignans.
Figure 4

Lignans.

2.8 Chromones/coumarins

Chromone derivatives 92103 were isolated from different species of Amaryllidoideae (Table 1 and Figure 5). Glucosylated derivatives at C7, viz., 100 and 101, at C5 (99), and the rare C6-C-glucose derivative (102, biflorin) were isolated from P. biflorum [46]. Compound 101 displayed weak anti-migratory and good antiproliferative activities against the highly metastatic prostate human cells (PC-3M) at 50 μM [46,47]. Biflorin (102) showed a wide spectrum of biological activities, especially against cancer [48].

Figure 5 
                  Chromones/coumarins.
Figure 5

Chromones/coumarins.

C. latifolium is a rare species and grows in Vietnam. The local people used the plant for the treatment of cancer. The coumarin derivative 4-[(senecioyloxy)methyl]-6,7-dimethoxycoumarin (104) was isolated as a bioactive constituent, which showed strong antiangiogenic activity and inhibited 76.6% of the tube-like formation of HUVECs at 3.0 μg/mL with no toxicity against B16F10 and HCT116 cell lines [49]. The obtained results justify the traditional uses of the plant for the treatment of cancer.

2.9 Phenylethanoids and phenylpropanoids

Phenylethanoids and phenylpropanoids are important building blocks in the biosynthesis of many natural products. Table 1 and Figure 6 illustrate the compounds reported from Amaryllidoideae. Non-glycosylated free forms such as tyrosol (105) and/or glucosyl/methyl/ethyl ethers have also been isolated. Mono (108, 109, 112, 113, 118, and 121) and diglucoside (110, 111, 114, 119, 120) derivatives were among the isolated compounds.

Figure 6 
                  Phenylethanoids and phenylpropanoids.
Figure 6

Phenylethanoids and phenylpropanoids.

{[7S]-7-(4-Hydroxyphenyl)-7-hydroxypropyl}-2′-methylbenzene-3′,6′-diol (123) isolated from L. aurea and showed neuroprotection against H2O2/CoCl2-induced neuronal cell death in dopaminergic neuroblastoma SH-SY5Y cells [10].

The extract of flowers of N. tazetta var. chinensis showed antimelanogenic activity. Pure compounds 108, 111, 114, 118, and 120 were isolated as active constituents and exhibited potent activity against theophylline-stimulated melanogenesis in B16 melanoma 4A5 cells at nontoxic concentrations [50], the isolated compounds have both lipophilic and hydrophilic characteristics and represent an ideal model for drug discovery with potent activity and selectivity.

2.10 Phenolic acids

The majority of isolated phenolic acids have the phenylpropanoid skeleton (Table 1 and Figure 7). The bulbs of C. asiaticum L. var. sinicum have been used to treat abscesses, aching joints, and sores in China. Phytochemical studies resulted in the isolation of different derivatives of benzoic (125, 126) and cinnamic (137, 139, and 140) acids [51,52], while caffeic (137) and dihydrocaffeic (131) acids were isolated from the flowers of H. vittatum [53].

Figure 7 
                  Phenolic acids.
Figure 7

Phenolic acids.

Chlorogenic (128) and neochlorogenic (129) acids were isolated from the flowers of N. tazetta var. chinensis [50], while piscidic acid (127) was isolated from the bulbs of N. poeticus [54].

Chlorogenic acid methyl ester (130) was isolated from P. maritimum and showed moderate inhibitory activity (43%) against M. tuberculosis H37Rv at 12.5 µg/mL, and potent cytotoxicity against HeLa cells with IC50 = 1.0 µg/mL [55].

The chlorogenic acid family belongs to the caffeoyl acid esters of quinic acid, which is widely distributed in nature and showed interesting biological activities [56,57].

Detection of phenolic acids by LC-MS and HPTLC was reported. Compounds such as 126, 131, 137, protocatechuic, vanillic, syringic, and ferulic acids were detected in the extracts of P. maritimum, Sternbergia colchiciflora, G. nivalis, G. elwesii, and Leucojum aestivum [58]. Chlorogenic acid (128) was found in the flowers of Narcissus cultivars and bulbs of C. woodrowii [29,59]. In addition, 135, ferulic, and coumaroyl quinic acid derivatives were detected in P. maritimum [60]. Furthermore, 137, protocatechuic, vanillic, syringic, gallic, m-hydroxybenzoic, sinapic, genistic, and salicylic acids were detected in Cryptostephanus vansonii and S. puniceus [61,62]. Vanillic and sinapic acids were identified as major phenolic acids from the leaves, flowers, and shoots of the Iranian G. transcaucasicus [63]. The ferulic and genistic acids were detected in the aerial parts of G. nivalis, N. pseudonarcissus, N. poeticus, and L. vernum [64].

2.11 Acetophenones

4-Hydroxyacetophenone was isolated as either its methoxylated and/or glycosylated derivative from Amaryllidoideae (Table 1 and Figure 8). Piceol (147) represents the simplest structure of the acetophenones and was isolated from Boophone disticha, C. buphanoides, and C. graminicola [65,66]. Nine glycosylated acetophenones (148156) were isolated from Haemanthus multiflorus, and 148 showed cytotoxic activity against the HL-60 cell line (IC50 = 20.1 μM) [67]. From P. biflorum, compounds 146, 155, and 156 were isolated and it was found that 155 and 156 showed growth-stimulating activity and enhanced the viability of Ehrlich ascites tumor cells. On the other hand, the same compounds (155 and 156) had no activity on the production of prostaglandin synthetase and 5-lipoxygenase [46,68].

Figure 8 
                  Acetophenones.
Figure 8

Acetophenones.

2.12 Terpenoids

Terpenoids have been poorly studied among the Amaryllidoideae, especially mono-, sesqui-, and diterpenoids. A few compounds belonging to different classes of triterpenes were reported in addition to the sesquiterpene (184). To the best of our knowledge, 28 terpenoids have been reported so far. Triterpenes having lupane, ursane, and oleanane skeletons have been identified. In addition, terpenes with different skeletons of the phytosterols having different substitution patterns at C4, C14, and C24 have also been reported (Table 1 and Figure 9).

Figure 9 
                  Terpenoids* (*the conventional numbering system is followed in this article).
Figure 9

Terpenoids* (*the conventional numbering system is followed in this article).

Phytosterols (C24 alkyl-substituted sterols), e.g., ergostane and stigmastane, are the most abundant sterols in the plant kingdom [69,70]. Cholestane is commonly accumulating in animals; however, some related compounds have been reported from certain species of higher plants [71]. The first examples of cholestanes (158, 162) isolated from Amaryllidoideae have recently been isolated from B. haemanthoides [72].

Compounds 165 and 169 were isolated from B. disticha bulbs and both compounds showed low activity against human neuroblastoma (SH-SY5Y) cells with IC50 values of 173.0 and 223.0 μM, respectively [73].

β-Sitosterol 3-glucoside (172) was isolated from C. purpurascens and it showed weak antibacterial activity against ST and SPB (MIC = 200 and 250 µg/mL) [74].

The sesquiterpene, parthenicin (184), was isolated from C. ensifolium and it showed strong cytotoxic activity against a selection of cancer cell lines and strongly inhibited NF-κB activity with an IC50 value of 1.82 μM [75].

2.13 Glycolipids and ceramides

Sphingolipids are derived from long-chain 1,3-dihydroxy-2-amino bases and they display good potential therapeutic effects. Glycolipids 196 and 197 were isolated from H. vittatum [76], in addition to the five ceramide glucosides (191195) [77] (Table 1 and Figure 10).

Figure 10 
                  Glycolipids/ceramides.
Figure 10

Glycolipids/ceramides.

Ceramides 185190 were isolated from Z. candida. It was found that 185 and 187 displayed moderate antibacterial activity against StA, EC, AN, CA, and TR [78,79].

2.14 Miscellaneous compounds

Vanillin (203) was isolated from C. bulbispermum [8] and its 4-glucoside derivative, amabiloside (204), was isolated from C. amabile [80]. Aliphatic hydroxyketones (220224) were isolated from C. augustum, grown in Egypt (Table 1 and Figure 11) [23,39].

Figure 11 
                  Miscellaneous compounds.
Figure 11

Miscellaneous compounds.

6-Hydroxy-2H-pyran-3-carbaldehyde (210) was isolated from C. yemense and it showed strong inhibition of the tyrosinase enzyme at a concentration of 42.2 μM [81]. In addition, benzyl glucoside (205), isolated from N. tazetta var. chinensis, showed potent anti-melanogenesis activity in the theophylline-stimulated B16 melanoma 4A5 cells with an IC50 of 59.0 μM [50].

4-(Hydroxymethyl)-5-hydroxy-2H-pyran-2-one (212) was isolated from S. pseudocaulus and it showed antibacterial activity against EC, PA, CA, CN, CP, and SF (MIC range: 4–64 μg/mL) and antioxidant activity using the DPPH assay (IC50 of 59.5 μM), and inhibited BuChE with an IC50 of 23.5 μM [24,45].

3 Conclusion

This review has brought comprehensive information about the non-alkaloidal chemical composition and biological activities of the plants belonging to the subfamily Amaryllidoideae. Such knowledge is of importance in the understanding of how plants can have an impact on human health or diseases (Figure 12).

Figure 12 
               Different types of secondary metabolites from Amaryllidoideae. The general profile of the secondary metabolites distribution among Amaryllidoideae shows the domination of alkaloids with 74%. Other metabolites like flavanoids, terpenoids, etc., share a lower percentage.
Figure 12

Different types of secondary metabolites from Amaryllidoideae. The general profile of the secondary metabolites distribution among Amaryllidoideae shows the domination of alkaloids with 74%. Other metabolites like flavanoids, terpenoids, etc., share a lower percentage.

Plants belonging to the Amaryllidoideae subfamily have a unique alkaloidal chemical composition making them different from the two Amaryllidaceae subfamilies, Agapanthoideae and Allioideae.

Considering the high alkaloidal content in the bulbs of the studied plant, it is interesting to note that the majority of the isolated compounds have been documented from the bulbs as well (45 plants, 81%) and contribute synergistically to the final biological effects of the bulbs, the most widely used plant part by traditional healers.

Currently, about 224 non-alkaloidal compounds (as listed above, and Figures 13 and 14) have been identified and belong to different classes of compounds. Most importantly, different chemical trends among the isolated compounds have been identified, which make this subfamily unique not only for its alkaloidal content but also for the other metabolites such as flavonoids, terpenoids, and ceramides.

Figure 13 
               Non-alkaloidal secondary metabolites distribution among Amaryllidoideae. The distribution of the non-alkaloidal secondary metabolites among different genus studied so far from Amaryllidoideae shows the highest number of isolated compounds coming from Crinum genus followed by Narcissus. Also, the figure shows that flavonoids (yellow blocks) are the most distributed class of compounds.
Figure 13

Non-alkaloidal secondary metabolites distribution among Amaryllidoideae. The distribution of the non-alkaloidal secondary metabolites among different genus studied so far from Amaryllidoideae shows the highest number of isolated compounds coming from Crinum genus followed by Narcissus. Also, the figure shows that flavonoids (yellow blocks) are the most distributed class of compounds.

Figure 14 
               Non-alkaloidal secondary metabolites of Amaryllidoideae. The profile of the non-alkaloidal secondary metabolites distribution shows the domination of flavonoids with 38%.
Figure 14

Non-alkaloidal secondary metabolites of Amaryllidoideae. The profile of the non-alkaloidal secondary metabolites distribution shows the domination of flavonoids with 38%.

The biosynthesis of phenylmethanoids (C6–C1), phenylethanoids (C6–C2), phenylpropanoids (C6–C3), acetophenones (C6–C2), chromones (C6–C4), and flavonoids (C6–C3–C6) could be derived from the shikmic acid pathway and directly related to the alkaloid biosynthesis through belladine (C6–C1–N–C2–C6), which is the commonly accepted precursor of the Amaryllidoideae alkaloids.

Although relatively fewer terpenoids have been isolated, the presence of different skeletons of phytosterols including cholestane is very significant. The phytosteroidal saponins were reported from the subfamily Allioideae as active constituents and taxonomical biomarkers. The presence of saponin aglycons in the Amaryllidoideae subfamily may represent a limited but important chemical bridge between the two subfamilies.

Among the flavonoids, many lipophilic flavans/flavanols were isolated from both aerial parts and bulbs. The lipophilic character increases the bioavailability of the flavans in the human diet and thereby boosts the therapeutic effects. On the other hand, mono-, di-, and triglycosides of flavonol and acetophenones were isolated mainly from flowers.

The activities of 1, 7, 15, 19, 90, and 146 against HL-60 (human promyelocytic leukemia cells) with IC50 ranged from 13.8 to 42.6 μM indicating the importance of discovery/design derivatives with the same chemical scaffold for treatment of such grave disease.

The updated knowledge on Amaryllidoideae chemistry and pharmacological activity has considerable opportunity for future discoveries. Relatively few species have been studied extensively for non-alkaloidal contents, and are mainly from China and Japan. Currently, there is little consistency in the compounds studied in different species. While few studies attempt to characterize the non-alkaloidal active components, it appears to be universally assumed that the alkaloids “only” are responsible for the pharmacological activity.

Further research on different aspects of Amaryllidoideae chemistry is also necessary to discover the new chemical/biological aspects of the subfamily, especially non-alkaloidal contents. Currently, from the 55 plant species under this review, limited numbers of biological studies are performed and represent ∼23% (13 plants). It is possible that other compounds are overlooked due to the alkaloid-oriented studies. For example, there are ∼1,000 research articles on alkaloids while only 40 on flavonoids. The reported 224 non-alkaloidal metabolites were isolated from less than 7% (55 plants) of the subfamily species, which indicates that a reasonable concentration of these metabolites is present in comparison to alkaloids and the method of phytochemical studies needs to be changed for more generic schemes than the alkaloid-focus method.

A more holistic approach to the study of Amaryllidoideae chemistry is necessary to further research on the subfamily. The current research tends to focus on alkaloids in different bulbs but fails to look at other parts such as leaves and flowers.

The presence of such a wide range of important biologically active non-alkaloidal compounds should encourage more investigation in the near future to fully understand the chemical profile of this subfamily and thereby discover their biological potential for human health benefits.

List of Abbreviations

AN

Aspergillus niger

A549

human lung cancer

B16F10

murine melanoma

BuChE

butyrylcholinesterase enzyme

CA

Candida albicans

CIELab

color space defined by the International Commission on Illumination

CN

Cryptococcus neoformans

CP

Candida parapsilosis

DPPH

2,2-diphenyl-1-picrylhydrazyl

EC

Escherichia coli

EF

Enterococcus faecalis

FRAP

ferric-ion reducing antioxidant power

HCT116

human colon carcinoma

HeLa

human cervical carcinoma

HepG2

hepatocellular carcinoma cell line

HL-60

human promyelocytic leukemia cells

HPTLC

high-performance thin layer chromatography

HUVECs

human umbilical vein endothelial cells

IC50

half-maximal inhibitory concentration

LC-MS

liquid chromatography coupled with mass spectrometer

Molt 4

child T-cell leukemia

NF-κB

nuclear factor kappa B

PA

Pseudomonas aeruginosa

PC-3M

metastatic human prostate cancer cells

PM

Proteus mirabilis

RAW264.7

mouse macrophages

M. tuberculosis H37Rv

Mycobacterum tuberculosis H37Rv

StA

Staphylococcus aureus

SF

Shigella flexneri

SH-SY5Y

human neuroblastoma cell line

SK-BR-3

human breast cancer

SPB

Salmonella paratyphi B

ST

Salmonella typhi

TR

Trichophyton rubrum


tel: +27‐21‐959‐6193; fax: +27‐21‐959‐3055

  1. Funding information: A.S. was financially supported by Embassy of Libya. The National Research Foundation (NRF) with a grant number 106055 under Professor Ahmed A. Hussein.

  2. Author contributions: A.H.: conceptualization; A.H., A.S.I, and A.O.A.: formal analysis and data collection; A.S.I. and A.O.A.: first draft; A.O.A. and A.H.A.: final draft and revision.

  3. Conflict of interest: The authors declare no conflict of interest.

  4. Ethical approval: The conducted research is not related to either human or animal use.

  5. Data availability statement: All data generated or analyzed during this study are included in this published article.

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Received: 2022-08-18
Revised: 2022-10-17
Accepted: 2022-11-09
Published Online: 2023-04-18

© 2023 the author(s), published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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